Pharmaceutical composition containing R-α-lipoic acid or S-α-lipoic acid as active ingredient

ABSTRACT

Pharmaceutical compositions and processes for their preparation containing R-α-lipoic acid or S-α-lipoic acid or pharmaceutically acceptable salts thereof. The pharmaceutical compositions have a cytoprotective activity and are suitable for combatting pain and inflammation.

This is a division of application Ser. No. 07/935,656, filed on Aug. 26,1992, now abandoned, which was a continuation of 07/610,215 filed Nov.8, 1990, which is now abandoned.

The present invention relates to pharmaceutical compositions containingR-α-lipoic acid or S-α-lipoic acid as an active ingredient. Thecompositions are useful because they inhibit, for example, acuteinflammation as well as inflammatory pain and they possess a specificcytoprotective activity.

BACKGROUND OF THE INVENTION

α-lipoic acid is 1,2-dithiacyclopentane-3-valeric acid. α-lipoic acid iswidely distributed in plants and animals in the form of theR-enantiomer; it acts as coenzyme in many enzymatic reactions,constitutes a growth factor for a number of bacteria and protozoa and isused in death-head fungus poisoning. In addition, the α-lipoic acidracemate displays anti-inflammatory, antinociceptive (analgesic) andcytoprotective properties.

SUMMARY OF THE INVENTION

It has now surprisingly been found that, in the case of the purelyoptical isomers of α-lipoic acid (R- and S-form, i.e. R-α-lipoic acidand S-α-lipoic acid), unlike the racemate, the R-enantiomer mainly hasan anti-inflammatory activity and the S-enantiomer mainly has anantinociceptive activity, the anti-inflammatory activity of theR-enantiomer also, for example, being stronger by a factor of 10 thanthat of the racemate. The antinociceptive (analgesic) activity of theS-enantiomer is for example stronger by a factor of 5 to 6 than that ofthe racemate. The enantiomers therefore constitute very much morespecific and stronger acting active substances than the racemate.

The following differences exist in particular in comparison to α-lipoicacid, i.e. to the racemate:

The R-enantiomer acts mainly as an anti-inflammatory and theS-enantiomer mainly as an analgesic, the optical isomers of α-lipoicacid being a number of times stronger (for example by at least a factorof 5) than the racemate of -lipoic acid.

It is therefore an object of the present invention to provide improvedpharmaceutical compositions which have, in particular, analgesic andanti-inflammatory activity.

The invention relates to pharmaceutical compositions containing asactive ingredient either R-α-lipoic acid or S-α-lipoic acid (i.e. theoptical isomers of α-lipoic acid) or a pharmaceutically acceptable saltof these optical isomers of α-lipoic acid, the preparation thereof andthe use of the optical isomers of α-lipoic acid or salts thereof for thepreparation of appropriate pharmaceutical compositions. These areparticularly suitable for combatting pain and inflammation. Acytoprotective activity is also obtained.

The amounts by weight set out herein relate, in each case, to the purelyoptical isomers of α-lipoic acid, i.e. not to the salts. When salts areused, the appropriate amounts must correspond in each case to theamounts of the free acid and be increased according to thegram-molecular weight of the salt.

The optical isomers of α-lipoic acid, i.e. R-α-lipoic acid andS-α-lipoic acid are preferably used as free acids. In aqueous solutionsthe salts are preferably used with pharmaceutically acceptable saltformers.

The preparation of R-α-lipoic acid and S-α-lipoic acid and of saltsthereof is effected in known manner or in an analogous manner.

Salt formers that may be considered for R-α-lipoic acid and S-α-lipoicacid are, for example, conventional bases or cations which arephysiologically acceptable in the salt form. Examples include: alkalimetals or alkaline earth metals, ammonium hydroxide, basic amino acidssuch as arginine and lysine, amines having the formula NR₁ R₂ R₃ inwhich the radicals R₁, R₂ and R₃ are the same or different and representhydrogen, C₁ -C₄ -alkyl or C₁ -C₄ -oxyalkyl, such as mono- anddiethanolamine, 1-amino-2-propanol, 3-amino-1propanol; alkylene diaminewith an alkylene chain consisting of 2 to 6 carbon atoms, such asethylenediamine or hexamethylene tetramine, saturated cyclic aminocompounds having 4-6 ring carbon atoms such as piperidine, piperazine,pyrrolidine, morpholine; N-methylglucamine, creatine, tromethamine.

In, for example, the acid writhing pain test in the mouse and in theRandall-Selitto inflammatory pain test in the rat, the S-enantiomer(S-α-lipoic acid) displays an analgesic activity (peroral application)which is superior by at least a factor of 5 or 6 to that of α-lipoicacid (i.e. the racemate).

Thus, for example, the above mentioned acid writhing test yielded ananalgesically active ED₅₀ of the S-α-lipoic acid of 10.2 mg/kg per os(ED₅₀ of the racemate 51.3 mg/kg per os). In the above mentionedRandall-Selitto test, the analgesically effective ED₅₀ of S-α-lipoicacid is 7.5 mg/kg per os (ED₅₀ of the racemate 45.9 mg/kg).

In, for example, carragheen-induced oedema in the rat the R-enantiomer(R-α-lipoic acid) shows an anti-inflammatory activity (peroralapplication) which is superior by at least a factor of 10 to that ofracemic α-lipoic acid.

For example, the above mentioned carragheen-induced oedema test yieldedan anti-inflammatorily active ED₅₀ of the R-enantiomer of 4.9 mg/kg peros (ED₅₀ of the racemate 49.7 mg/kg).

The minimum analgesically effective dose of S-α-lipoic acid in theRandall-Selitto pain test is, for example, 1 mg/kg per os.

The minimum anti-inflammatorily effective dose of R-α-lipoic acid in thecarragheen-induced oedema test is, for example, 1 mg/kg per os.

Similarly, both the R- and the S-form display cytoprotective activity inanimal experiments with a dose of as little as 10 mg/kg per os.

In addition, R- and S-α-lipoic acid surprisingly possess agrowth-inhibiting activity against retroviruses, in particular humanimmunodeficiency virus HIV (HIV-1, HlV-2) and are, therefore, alsosuitable for the treatment of disorders caused by viruses of this type.

They possess a good growth-inhibiting activity in HIV (Types 1 and 2)which may be demonstrated in vitro for example by means of the followingvirological and cell biological test procedures:

1. Plaque reduction test

2. CPE reduction test

3. Determination of reverse transcriptase in culture supernatant

4. Determination of p24 antigen in culture supernatant

Thus, for example, a single dose of 0.035 mg/ml reduces the number ofinfectious viruses (for example HIV-1) in cell culture supernatant from100% in the positive control to 0%. A virus-inhibiting activity can bedemonstrated in this test procedure even in very small doses, forexample 0,001 mg/ml.

The general dosage range for the activity (experiment as above) may forexample be: 0.0035-0.091 mg/ml, in particular 0,035-0.070 mg/ml.

In the case of the in vitro experiments the active ingredient is used,for example in benzyl alcohol as solvent.

The following substrates may, for example, be used for the in vitroinvestigations of the replication behavior of retroviruses, inparticular HIV:

1. Virus-containing RPMI 1640 medium, for example 1× liquid 041-01875(synthetic culture medium from Gibeo according to Moore, Gerner andFranklin, H. A. (1967), J.A.M.A. 199; 519) in a concentration of 2×10³-1×10⁴ infectious units (PFU)/ml

2. The cell lines Jurkat Clone E6-1, Sup T1 and HeLa CT4.

The pharmaceutical formulations contain in general between 50 mg to 3 gas a single dose, preferably 100 mg to 1 g of R- or S-α-lipoic acid. Thedose per kg of body weight should be between 3.5 and 200 mg, preferablybetween 7 and 100 mg, in particular between 35 and 70 mg/kg body weight.

The active ingredient should be released slowly from the formulations.

Administration may for example be in the form of tablets, capsules,pills, coated tablets, aerosols or suppositories, or in liquid form.

Liquid forms of application that may, for example, be considered are:alcoholic or aqueous solutions as well as suspensions and emulsions.

Preferred dosage forms are, for example, tablets containing between 100mg and 2 g or solutions containing between 10 mg to 2 g/ml of liquid ofactive ingredient.

The single dose of active ingredient of may for example be:

a) in the oral medicinal form between 100 mg-3 g, preferably 200 mg-1 g.

b) in parenteral medicinal forms (for example intravenous,intramuscular) between 100 mg-12 g, preferably 200 mg-6 g.

c) in medicinal forms for inhalation (solutions or aerosols) between 100mg-2 g, preferably 200 mg-1 g.

d) in medicinal forms for rectal or vaginal application between 100 mg-2g, preferably 200 mg-1 g.

The doses according to a) to d) may for example be administered 1 to 6times, preferably 1 to 4 times daily or, however, as a permanentinfusion, for example with the aid of an infusoniate, i.e., with aninfusion apparatus for accurate hourly dosage of an active substance insolution.

The daily dose of R- or S-α-lipoic acid in humans should for example bebetween 70-80 mg per kg weight; the single dose for example 16-20 mg perkg body weight, this dose appropriately being given 4 times daily: thepharmaceutical compositions therefore preferably contain 1-1.5 g of R-or S-α-lipoic acid in a pharmaceutical formulation, a dose of this typepreferably being given 4 times each day.

The recommended treatment is, for example, 3 times daily, 1 to 4 tabletswith a content of 50 mg to 2 g of active ingredient per tablet, or, forexample, in intravenous injection 1 to 4 times daily, oneampoule/infusion bottle of 1 to 500 ml content with 200 mg to 6 g ofactive ingredient. In the case of oral administration the minimum dailydose is for example 300 mg; the maximum daily dose, given orally, shouldnot exceed 12 g.

The pharmaceutical compositions may be used in human medicine alone orin a mixture with other pharmacologically active ingredients. The activeingredients R- or S-α-lipoic acid may also be combined with any otheragent effective against retroviruses, in particular HIV, for examplewith didesoxyinosin, didesoxycytidine, in particular, however, withα-interferon and/or azidothymidine (AZT).

The dose amounts mentioned refer, in each case, to the free acids R- orS-α-lipoic acid. Should these be used in the form of their salts, thequoted dosages/dosage ranges should be increased in accordance with thehigher molecular weight of the salts.

In the case of combinations with other antiretrovirally actingsubstances (component b) not only one, but also 2 and more (preferably2) antiretrovirally active ingredients may be used as component b, thedosages cited therefor always referring to the sum of theantiretrovirally active ingredients present in each case.

The expression "dosage unit" always refers to a single dose which mayalso be administered several times daily.

If the dose is quoted in the form of enzyme units, this is the doseapplicable for an entire day. A dose of this kind may be given once eachday, but preferably is spread out over a whole day (for example ininfusion form). The dose information in enzyme units applies inparticular to α-interferon.

For the combination of R- or S-α-lipoic acid with the component b forexample AZT, the two components may in each case be mixed for example ina ratio of 1 to 100 to 100 to 1 equimolar parts of active ingredient, inparticular in a ratio of 1 to 10 to 10 to 1, preferably in a ratio of 1to 3 to 3 to 1 parts.

In the case of a combination of R- or S-α-lipoic acid and α-interferonthe two components may for example be present in the following ratio: 50mg-6 g of R- or S-α-lipoic acid (component a) to 8×10⁶ enzyme units to1×10⁵ enzyme units of α-interferon, in particular 0.5-3 g of component ato 1-4×10⁶ enzyme units of α-interferon.

In the combination of R- or S-α-lipoic acid and other components inaccordance with b), both components may be present as a mixture. Ingeneral, the components are, however, separated from one another in onepharmaceutical formulation, the pharmaceutical formulations known forthis purpose being suitable for this purpose: for example one componentas tablet or lacquered tablet, the other component as powder, both inone capsule and vice versa; one component in the form of pellets, theother as powder, coated tablet or talet and vice versa so that the twoforms are present, for example, in one capsule; or in the form ofmulti-layer or laminated tablets. Reference is made in this context forexample to the book "Arzneimittelstabilitat" by Karl Thoma, Frankfurt1978, for example page 207 et seq.

The combination of the invention may, however, also be present as aproduct in which in each case the two individual active ingredients maybe present in formulations totally separated from one another, wherecomponent b in particular, but also both components (a and b) arecontained in ampoules and/or infusion bottles, so that administrationmay occur separately or also at different times.

If totally different formulations of this type are present, these areadapted to each other and contain the appropriate active ingredients inthe dosage unit in the same amounts and corresponding weight ratios inwhich they may be present in the combined mixture.

In the case of a product for separate use, it is also possible for bothcomponents of the combination to be administered at different times. Insuch cases it is for example possible to give R- or S-α-lipoic acid as apermanent infusion (dose for example 2-5 g per day) and the othercomponent b to be given at the same time (dose for example 50-800 mg or1-8×10⁶ enzyme units, preferably intramuscularly) or also as permanentinfusion per day or R- or S-α-lipoic acid may, for example, be given 4times daily (single dose for example 0.5-2 g) and the other component bat the same time (dose for example 50-200 mg or 0.5-3×10⁶ enzyme units).It is then possible for example for 1 to 3 further doses of component b(for example between 50-200 mg or 0.5-3×10⁶ enzyme units) to followafter an interval of, in each case, 6 and/or 12 hours.

The formulations/products of the invention may preferably also containadditional vitamins, in particular vitamin B₁ and/or vitamin E.

For the treatment of disorders caused by retroviruses, in particular HIVviruses, appropriate pharmaceutical compositions should contain such anamount of R- or S-lipoic acid or this should be administered in such anamount, that single or repeated application achieves in the body a levelof activity between 3.5 and 200 mg/kg, preferably 7 and 100 mg, inparticular between 35 and 70 mg/kg body weight.

For the analgesic activity the general dose range of S-α-lipoic acidthat may be considered is, for example:

    1-100 mg/kg orally.

For the anti-inflammatory and cytoprotective activity the general doserange of R-α-lipoic acid that may be considered is, for example:

    1-100 mg/kg orally.

Apart from its antinociceptive (analgesic) main activity, S-α-lipoicacid also possesses an anti-inflammatory and cytoprotective activity,however to a lesser extent.

In addition to the main anti-inflammatory and anti-arthritic activity,R-α-lipoic acid also has antinociceptive and cytoprotective activity,albeit to a lesser extent.

The optical isomers of α-lipoic acid display a good analgesic,anti-inflammatory, anti-arthrotic and cytoprotective activity in, forexample, the following investigatory models:

MgSO₄ writhing test in the mouse according to GYIRES et al. (Arch. int.pharmacodyn. therap. 267, 131-140 (1984))

Adjuvans arthritis in the rat according to NEWBOULD (Brit. J. Pharmacol.21, 127-136 (1963))

TPA- or arachidonic acid-induced mouse ear oedema according to YOUNG etal. (J. Invest. Dermatol. 80, 48-52 (1983))

Na-mono-iodazetate-induced arthrosis in rats or chickens according toKALBHEN in: Arthrosis deformans, EularVerlag, Basel/Switzerland, 1982

TPA-induced arthrosis in rats according to WEISCHER (Agents and Actions23, 1/2 (1988))

Intestinal ulcerations in rats according to DEL SOLDATO (Agents andActions 16, 393-396 (1985))

Colitis-model in the rat according to WEISCHER at al (Agents andActions, vol. 26, 1/2, page 222 to 223, (1989))

Ethanol-ulcer model in the rat (determination for example of acytoprotective activity).

The optical isomers of α-lipoic acid inhibit for example acuteinflammation as well as inflammatory pain and they possess a specificcytoprotective activity.

Indications that may for example be considered are:

Inflammatory, degenerative articular and extra-articular rheumaticdisorders, non-rheumatic states of inflammation and swelling, Arthrosisdeformans, chondropathies, periarthritis, inflammatory andnon-inflammatory skin disorders such as for example neurodermitis andpsoriasis, inflammatory and non-inflammatory disorders of thegastro-intestinal tract, such as for example gastritis, Ulcusventriculi, ileitis, duodenitis, jejunitis, colitis, polyneuropathy ofdiabetogenic, alcoholic, hepatic and uraemic origin, degeneration of theliver parenchyma, hepatitis, fatty liver and fatty cirrhosis as well aschronic liver disorders, inflammatory respiratory tract disorders, suchas bronchial asthma, sarcoidosis, ARDS (acute respiratory distresssyndrome).

The daily doses of the dosage forms of the invention for analgesic orcytoprotective or anti-inflammatory activity are, for example, 0.1 to600 mg, preferably 15 to 400 mg and in particular 50 to 200 mg ofR-α-lipoic acid or S-α-lipoic acid.

In accordance with the invention the optical isomers of α-lipoic acid(R- or S-form in each case) are given in a daily dose of 10-600 mg, forexample of 25 to 400 mg or 10 to 200 mg. The maximum daily dose for thecytoprotective activity and for the treatment of pain and inflammationshould not exceed 600 mg. The daily doses may be given in the form of asingle administration of the total amount or in the form of 1 to 6, inparticular 1-4, partial doses per day. In general an administration of1-4 times, in particular 1-3 times daily is preferred.

For example the preferred daily dose of both R-α-lipoic acid andS-α-lipoic acid is preferably 80 mg for the parenteral form ofapplication and 200 mg for the oral form. In particular the daily dosefor the parenteral form of application is 50 mg and 150 mg for the oralform.

The pharmaceutical compositions are preferably administered orally.

R-α-lipoic acid and S-α-lipoic acid may in particular also be applied inthe form of a solution, for example perorally, topically, parenterally(intravenously, intraarticularly, intramuscularly, subcutaneously), asan inhalation, rectally, transdermally or vaginally.

Pharmaceutical compositions containing R-α-lipoic acid or S-α-lipoicacid as active ingredient may for example be formulated in the form oftablets, capsules, pills or coated tablets, granulates, pellets,plasters, solutions or emulsions, the active ingredient in each caseoptionally being combined with appropriate auxiliary and carriersubstances. In the case of solutions, these contain for example 0.5 to20% by weight, preferably 1 to 10% by weight of one of the opticalisomers of α-lipoic acid (in each case either the R-form or S-form).

The dosage unit of the pharmaceutical composition with the opticalisomers of α-lipoic acid or a therapeutically useful salt thereof (ineach case either the R-form or the S-form) may, for example, contain:

a.) in the case of oral medicinal forms:

10 to 600 mg, preferably 20 to 400 mg, in particular 50 to 200 mg of theoptical isomers of α-lipoic acid. The doses may for example be given 1to 6 times, preferably 1 to 4 times, in particular 1 to 3 times daily.In each case, however, a total dosage of 600 mg per day should not beexceeded for the cytoprotective activity and for the treatment of painand inflammation. The same also applies to the following medicinal formslisted under b) to e).

b.) in the case of parenteral medicinal forms (for example intravenous,intramuscular or intra-articular):

10 to 300 mg, preferably 15 to 200 mg, in particular 20 to 100 mg of theoptical isomers of α-lipoic acid. The doses may, for example, be given 1to 6 times, preferably 1 to 4 times, in particular 1 to 3 times daily.

c.) in the case of medicinal forms for application to the skin andmucous membranes (for example as solutions, lotions, emulsions,ointments, plasters and the like):

10 to 500 mg of R-α-lipoic acid or S-α-lipoic acid, preferably 40 to 250mg, in particular 50 to 200 mg. These doses may for example beadministered 1 to 6 times, preferably 1 to 4 times, in particular 1 to 3times daily.

d.) In the case of medicinal forms for inhalation (solutions oraerosols):

0.1 to 300 mg, preferably 0.25 to 150 mg, in particular 0.5 to 80 mg ofR-α-lipoic acid or S-α-lipoic acid. These doses may, for example, beadministered 1 to 6 times, preferably 1 to 4 times, in particular 1 to 3times daily.

Should lotions be used, the optical isomers of α-lipoic acid arepreferably used in the form of a salt.

It is of course also possible to prepare pharmaceutical formulationswhich contain 2 to, for example, 6 times the above mentioned dosageunits. In particular the tablets or capsules contain 20 to 500 mg,pellets, powders or granulates 20 to 400 mg, suppositories 20 to 300 mgof R-α-lipoic acid or S-α-lipoic acid.

To combat retroviruses (for example AIDS) the daily dose is for example4-6 g. Corresponding pharmaceutical compositions therefore preferablycontain R-α-lipoic acid or S-α-lipoic acid in the single dose (doseunit) for example in an amount of 600 mg to 1.5 g.

The above mentioned dosages always relate to the free optical isomers ofα-lipoic acid. Should the optical isomers of α-lipoic acid be used inthe form of a salt, the dosages/dosage ranges should be correspondinglyincreased due to the higher molecular weight.

The acute toxicity of R-α-lipoic acid and S-α-lipoic acid in the mouse(expressed as the LD50 mg/kg; method of LITCHFIELD and WILCOXON, J.Pharmacol. Exp Ther. 95, 99 (1949)), is for example in excess of 100mg/kg in the case of oral administration.

In the event of the optical isomers of α-lipoic acid being used inanimals, the following indications may be considered in particular:hepatoses, Arthrosis deformans, arthritis and dermatitis.

The following dosages may for example be considered for the treatment ofanimals (both R-form and S-form):

For the treatment of cats, the oral single dose generally lies betweenabout 2 mg/kg and 50 mg/kg body weight, the parenteral dose aboutbetween 0.5 and 40 mg/kg body weight.

For the treatment of arthroses in horses and cattle, the oral singledose generally lies between about 2 mg/kg and 100 mg/kg body weight, theparenteral dose about between 0.5 and 50 mg/kg body weight.

The individual optical isomers of α-lipoic acid are suitable for thepreparation of pharmaceutical compositions and formulations. Thepharmaceutical compositions and/or pharmaceutical compositions containthe optical isomers of α-lipoic acid as active ingredient, optionally ina mixture with other pharmacologically and/or pharmaceutically activeingredients. The preparation of the pharmaceutical compositions iseffected in known manner, it being possible to use known andconventional pharmaceutical auxiliary substances as well as otherconventional carrier and diluting agents. Carrier and auxiliarysubstances of this type which may for example be considered are thoserecommended or quoted in the following literature references asauxiliary substances for pharmacy, cosmetics and associated fields:"Ullmanns Enzyklopadie der technischen Chemie, Volume 4 (1953), page 1to 39; Journal of Pharmaceutical Sciences", Volume 52 (1963), page 918et seq., H. v. Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie undangrenzende Gebiete"; Pharm. Ind. Issue 2 (1961), page 72 et seq.; Dr.H. P. Fiedler, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik undangrenzende Gebiete", Cantor KG, Aulendorf in Wurttemberg (1989).

The pharmaceutical and galenic treatment of the R- or S-α-lipoic acid iscarried out using conventional standard methods. For example R- orS-α-lipoic acid and auxiliary or carrier substances may be well mixed bystirring or homogenization (for example using conventional mixingapparatus), working generally being at temperatures between 20° and 50°C., preferably 20° to 40° C., in particular at room temperature. Forfurther particulars reference is made to the following standard work:Sucker, Fuchs, Speiser, "Pharmazeutische Technologie", Thieme-VerlagStuttgart, 1978.

Application of the R- or S-α-lipoic acid or of the pharmaceuticalcompositions may be to the skin or mucous membrane or to the inside ofthe body, for example oral, enteral, pulmonal, rectal, nasal, vaginal,lingual, intravenous, intra-arterial, intracardial, intramuscular,intraperitoneal, intracutaneous, subcutaneous administration.

The parenteral formulation forms are in particular sterile or sterilizedproducts.

If the R- or S-α-lipoic acid are used in the form of their salts, thesalt formers may also be used in excess, i.e. in an amount greater thanequimolar.

Examples of carrier and auxiliary substances are gelatin, natural sugarssuch as raw sugar or lactose, lecithin, pectin, starches (for examplecorn starch or amylose), cyclodextrins and cyclodextrin derivatives,dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginicacid, tylose, talcum, lycopodium, silicic acid (for example colloidal),cellulose, cellulose derivatives (for example cellulose ethers, in whichthe cellulose-hydroxy groups are partially etherified with lowersaturated aliphatic alcohols and/or lower saturated aliphaticoxyalcohols, for example methyloxypropyl cellulose, methyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulosephthalate);fatty acids as well as magnesium, calcium or aluminium salts of fattyacids with 12 to 22 carbon atoms, in particular saturated (for examplestearates), emulsifiers, oils and fats, in particular vegetable (forexample peanut oil, castor oil, olive oil, sesame oil, cottonseed oil,corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in eachcase also hydrated); glycerol esters and polyglycerol esters ofsaturated fatty acids C₁₂ H₂₄ O₂ to C₁₈ H₃₆ O₂ and their mixtures, theglycerol hydroxy groups being totally or only partially esterified (forexample mono, di and triglycerides); pharmaceutically acceptable singleor multivalent alcohols and polyglycols as well as polyethylene glycols(molecular weight range for example 300 to 1500) as well as derivativesthereof, polyethylene oxide, esters of aliphatically saturated orunsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms)or multivalent alcohols such as glycols, glycerol, diethylene glycol,pentaerythritol, sorbitol, mannitol and the like, which may optionallyalso be etherified, esters of citric acid with primary alcohols, aceticacid, urea, benzylbenzoate, dioxolanes, glycerol formals,tetrahydrofurfuryl alcohol, polyglycol ether with C₁ -C₁₂ alcohols,dimethylacetamide, lactamides, lactates, ethylcarbonates, silicons (inparticular medium-viscous polydimethylsiloxanes), calcium carbonate,sodium carbonate, calcium phosphate, sodium phosphate, magnesiumcarbonate and the like.

Other auxiliary substances that may be considered are those whichpromote disintegration (so-called disintegrants), such as: cross-linkedpolyvinylpyrrolidone, sodium carboxy methyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. It is also possible touse known coating substances. These may, for example, be: polymerizatesas well as copolymerizates of acrylic acid and/or methacrylic acidand/or their esters; copolymerizates of acrylic and methacrylic acidesters with a low ammonium group content (for example Eudragit^(R) RS),copolymerizates of acrylic and methacrylic acid esters andtrimethylammonium methacrylate (for example Eudragit^(R) RL); polyvinylacetate; fats, oils, waxes, fatty alcohols; hydroxypropylmethylcellulosephthalate or -acetate succinate; cellulose acetate phthalate, starchacetate phthalate as well as polyvinyl-acetate phthalate; carboxymethylcellulose; methylcellulose phthalate, methylcellulose succinate,-phthalate succinate as well as methylcellulose-phthalic acid halfester; zein; ethyl cellulose as well as ethylcellulose succinate;shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acidanhydride copolymer; maleic acid anhydride-vinylmethyl ether copolymer;styrol-maleic acid copolymerizates; 2-ethyl-hexyl-acrylate maleic acidanhydride; crotonic acid-vinylacetate copolymer; glutaminicacid/glutaminic acid ester copolymer;carboxymethylethyl-cellulose-glycerol monooctanoate; celluloseacetatesuccinate; polyarginin.

Plasticizing agents that may be used as coating substances are:

citric and tartaric acid esters (acetyltriethyl citrate,acetyltributyl-, tributyl-, triethyl citrate); glycerol and glycerolesters (glycerol diacetate, -triacetate, acetylated monoglycerides,castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-,dimethyl-, dipropyl phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalyl ethyl glycolateand butyl glycolate; alcohols (propylene glycol, polyethylene glycol ofvarious chain lengths), adipates (diethyl-adipate, di-(2-methoxy- or2-ethoxyethyl)-adipate); benzophenone; diethyl- and dibutylsebacate,dibutyl succinate, dibutyl tartrate; diethylene glycol diproprionate;ethylene glycoldiacetate, -dibutyrate, -dipropionate; tributylphosphate, tributyrin; polyethylene glycol sorbitan monooleate(polysorbates such as Polysorbat 80); sorbitan monooleate.

To prepare solutions or suspensions it is for example possible to usewater or physiologically acceptable organic solvents such as for examplealcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol,polyglycols and their derivatives, fatty alcohols, partial esters ofglycerol), oils (for example peanut oil, olive oil, sesame oil, almondoil, sunflower oil, soya bean oil, castor oil, cattle hoof oil),paraffins, dimethyl sulfoxide, triglycerides and the like.

For injectable solutions or suspensions it is for example possible touse non-toxic parenterally acceptable diluents or solvents, such as forexample: water, 1,3-butane diol, ethanol, 1,2-propylene glycol,polyglycols in mixture with water, glycerol, Ringer's solution, isotoniccooking salt solution or also hardened oils including synthetic mono- ordiglycerides or fatty acids such as oleic acid.

In preparing the formulations it is possible to use known andconventional solubilizers or emulsifiers. Solubilizers and emulsifierswhich may for example be used are: polyvinylpyrrolidone, sorbitan fattyacid esters such as sorbitan trioleate, phosphatides such as lecithin,acacia, tragacanth, polyoxyethylated sorbitan monooleate and otherethoxylated fatty acid esters of sorbitan, polyoxyethylated fats,polyoxyethylated oleotriglycerides, linolisated oleotriglycerides,polyethylene oxide condensation products of fatty alcohols, alkylphenolsor fatty acids or also 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2).Polyoxyethylated here means that the substances in question containpolyoxyethylene chains, the degree of polymerization of which generallylies between 2 and 40 and in particular between 10 and 20.Polyoxyethylated substances of this kind may for example be obtained byreacting hydroxyl group-containing compounds (for example mono- ordiglycerides or unsaturated compounds such as those containing oleicacid radicals) with ethylene oxide (for example 40 mol of ethylene oxideper 1 Mol glyceride).

Examples of oleotriglycerides are olive oil, peanut oil, castor oil,sesame oil, cottonseed oil, corn oil.

See also Dr. H. P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie,Kosmetik und angrenzende Gebiete" 1971, p. 191-195.

In addition, it is also possible to add preservatives, stabilizers,buffer substances, flavor correcting agents, sweeteners, colorants,antioxidants and complex formers and the like.

Complex formers that may for example be considered are: chelate formerssuch as ethylene diamine tetraacetic acid, nitrilotriacetic acid,diethylenetriamine pentaacetic acid and salts thereof.

Complex formers that may be considered include those which enclose theR- or S-α-lipoic acid acid in a hollow space. Examples hereof are urea,thiourea, cyclodextrins, amylose. The active molecule substance mayoptionally be stabilized With physiologically acceptable bases orbuffers to a pH range of ca. 6 to 9. Preference is in general given toas neutral or weakly basic a pH value as possible (up to pH 8).

Antioxidants that may for example be used are sodium sulphite, sodiumhydrogen sulphite, sodium metabisulphite, ascorbic acid, ascorbylpalmitate, -myristate, -stearate, gallic acid, gallic acid alkyl ester,butylhydroxyanisol, nordihydroguaiacic acid, tocopherols as well assynergists (substances that bind heavy metals through complex formation,for example lecithin, ascorbic acid, phosphoric acid ethylene diaminetetraacetic acid, citrates, tartrates). The addition of the synergistssubstantially enhances the antioxygenic activity of the antioxidants.

Preservatives that may for example be considered are sorbic acid,p-hydroxybenzoic acid esters (for example lower alkyl esters), benzoicacid, sodium benzoate, trichloroisobutyl alcohol, phenol, creosol,benzethonium chloride, chlorhexidine and formalin derivatives.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following is a brief description of the test methods used in theexperiments described below:

Randall-Selitto test (inflammatory pain in the rat)

By analogy with the method according to RANDALL and SELITTO (L. O.Randall and J. Selitto, Arch. int. Pharmacodyn. Vol. 111, pages 409-418(1957)), rats receive subplantar injections of 0.1 ml of a 20% (indemineralized water) brewer's yeast suspension into the right back paw.2 1/2 hours thereafter the test substances are administered and 30minutes thereafter the pain threshold (in grams) is measured as pain inthe inflamed paw using a commercially available algesia meter. Thecriterion is the defense reaction shown by the animals in pulling thepaw away and/or freeing themselves from the research worker's grip. Theactivity of the substance is measured in the form of the increase in thepain threshold as compared to an untreated control group. The course ofthe experiment differs from that in the original method in that thesubstances are only given 2-1/2 hours after provocation of the edema andnot simultaneously therewith. In so doing the intention is to preventthe development of the edema being inhibited by a possibleanti-inflammatory activity and masking or feigning analgesia.

The ED₅₀ is determined using the linear regression method. The ED₅₀ hereis the dose in mg/kg at which mathematically there is a 50% analgesicactivity.

Acetic acid test (writhing test) in the mouse

Method:

In the acetic acid test after KOSTER et al. (Fed. Proc., Vol. 18, page412 (1959)) the pain stimulus is triggered by an intraperitonealinjection of 1% acetic acid. The pain reaction is expressed in the formof the characteristic stretching of the animals ("writhing syndrome")which continues at irregular time intervals for some time afterinjection of the acetic acid. The dose-dependent inhibition of thefrequency of the stretching movement as compared to an untreated controlgroup is expressed in percent as analgesic activity. Evaluation is bydetermination of the ED₅₀ (Method of linear regression). The ED₅₀ is thedose in mg/kg at which there is a 50% inhibition of the "writhingsyndrome".

The acetic acid test is characterized in that it not only demonstratesthe activity of strong, centrally acting analgesics, but also that ofpredominantly peripherally active analgesic-antipyretic agents andanti-inflammatory pharmaceuticals, such as phenylbutazone, indomethacinand the like. The activity in the experimental design suggests aperipheral component of the analgesia.

Caragheen-induced edema test for anti-inflammatory activity:

The investigation is conducted in carragheen-induced edema of the ratpaw after the method of MOERSDORF and coworkers (Arch. int. Pharmacodyn.192, 111-127 (1971)). The anti-inflammatory activity is, for example,given as inhibition of edema in percent as compared to the untreatedcontrol group. Application is oral or intraperitoneal in allexperiments. The substance is administered orally or intraperitoneally 1hour after triggering the inflammation. The ED₅₀ is the dose in mg/kg atwhich there is 50% inhibition of the paw oedema.

EXAMPLE 1 Tablets Containing 50 mg of S- or R-α-Lipoic Acid

250 g of S-α-lipoic acid are evenly ground with 750 g ofmicrocrystalline cellulose. After sieving the mixture, 250 g of starch(starch 1500/Colorcon), 732.5 g of lactose, 15 g of magnesium stearateand 2.5 g of highly disperse silicon dioxide are mixed therein and themixture is pressed into tablets weighing 400.0 mg.

Each tablet contains 50 mg of S-α-lipoic acid.

In similar manner it is possible to prepare tablets containing 50 mg ofR-α-lipoic acid when the 250 g of lipoic acid is replaced by the sameamount of R-α-lipoic acid.

The tablets may optionally be provided with a gastric juice soluble orgastric juice permeable film coating using conventional methods.

EXAMPLE 2 Ampoules Containing 50 mg of S- or R-α-Lipoic Acid asTromethamine Salt in 2 ml

250 g of S-α-lipoic acid are dissolved with stirring together with 352.3g of tromethamine (2-amino-2- (hydroxymethyl)-1,3-propane diol) in amixture of 9 liters of sterile deionized water and 200 g of1,2-propylene glycol. The solution is diluted to 10 liters with steriledeionized water and then filtered through a membrane filter of pore size0.2 μm using a glass fiber pre-filter. The filtrate is filled underaseptic conditions in 2 ml batches into sterilized 2 ml ampoules.

One ampoule contains 50 mg of S-α-lipoic acid as tromethamine salt in 2ml of injection solution.

The same procedure may be used to prepare ampoules with R-α-lipoic acidby using the same amount of R-α-lipoic acid in place of 250 g ofS-α-lipoic acid.

What is claimed is:
 1. A pharmaceutical composition consistingessentially of a pharmaceutically effective carrier and, as activeingredient, an effective amount of R-α-lipoic acid or a pharmaceuticallyacceptable salt thereof.
 2. A pharmaceutical composition as set forth inclaim 1 which is a solution containing R-α-lipoic acid as activeingredient and also a member of the group consisting of stabilizers andsolubilizers.
 3. A pharmaceutical composition as set forth in claim 2 inwhich the stabilizer or solubilizer is selected from the groupconsisting of aliphatic C₂ -C₄ -alcohol which contain one, two or threehydroxyl groups, polyethylene glycol of molecular weights between 200and 600; conventional physiologically acceptable organic amide,natural - aminoacid, aliphatic amine, hydroxyethyl theophylline,tromethamine, diethyleneglycol monomethylether.
 4. A pharmaceuticaldosage unit containing the pharmaceutical composition set forth in claim1 in an amount such that the R-α-lipoic acid is in each case present inan amount of 0.1 mg to 6 g.
 5. A pharmaceutical dosage unit containingthe pharmaceutical composition set forth in claim 1 in an amount suchthat the R-α-lipoic acid is in each case present in an amount of 0.1 to600 mg.
 6. A tablet containing the pharmaceutical composition set forthin claim 1 in an amount such that the R-α-lipoic acid is in each casepresent in an amount of between 100 mg and 2 g.
 7. A dosage unit of asolution suitable for parental administration containing thepharmaceutical composition set forth in claim 1 in an amount such thatthe R-α-lipoic acid is in each case present in an amount of 100 mg-12 g.8. A dosage unit of a solution suitable for parental administrationcontaining the pharmaceutical composition set forth in claim 1 in anamount such that the R-α-lipoic acid is in each case present in anamount of 200 mg-6 g.
 9. A method of combatting inflammatory,degenerative articular and extra-articular rheumatic disorders,non-rheumatic states of inflammation and swelling, Arthrosis deformans,chondropathies, periarthritis, neurodermitis and psoriasis, gastritis,Ulcus ventriculi, ileitis, duodenitis, jejunitis, colitis,polyneuropathy of diabetogenic, alcoholic, hepatic and uraemic origin,degeneration of the liver parenchyma, hepatitis, fatty liver and fattycirrhosis as well as chronic liver disorders, bronchial asthma,sarcoidosis, ARDS (acute respiratory distress syndrome) which comprisesadministering an effective amount of the pharmaceutical composition ofclaim
 1. 10. The pharmaceutical composition of claim 3 wherein saidstabilizer is tromethamine.